RESUMEN
The National Institute of Mental Health (NIMH) has made sustained investments in the development of genomic resources over the last two decades. These investments have led to the development of the largest biorepository for psychiatric genetics as a centralized national resource. In the realm of genomic resources, NIMH has been supporting large team science (TS) consortia focused on gene discovery, fine mapping of loci, and functional genomics using state-of-the-art technologies. The scientific output from these efforts has not only begun to transform our understanding of the genetic architecture of neuropsychiatric disorders, but it has also led to a broader cultural change among the investigator community towards deeper collaborations and broad pre-publication sharing of data and resources. The NIMH supported efforts have led to a vast increase in the amount of genetic and genomic resources available to the mental health research community. Here we provide an account of the existing resources and estimates of the scale and scope of what will be available in the near future. All biosamples and data described are intended for broad sharing with researchers worldwide, as allowed by the subject consent and applicable laws.
Asunto(s)
Genómica , Trastornos Mentales/genética , Conducta Cooperativa , Genómica/métodos , Humanos , Difusión de la Información , Internet , Trastornos Mentales/metabolismo , National Institute of Mental Health (U.S.) , Conservación de Tejido , Estados UnidosRESUMEN
Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.
Asunto(s)
Variaciones en el Número de Copia de ADN , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/fisiopatología , Adolescente , Adulto , Anciano , Niño , Estudios de Cohortes , Conducta Cooperativa , Minería de Datos , Femenino , Predisposición Genética a la Enfermedad , Genoma , Humanos , Masculino , Persona de Mediana Edad , Modelos Genéticos , Modelos Neurológicos , Fenotipo , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Comunicación Académica , Adulto JovenRESUMEN
The objective of this analysis was to examine the genetic architecture of diverse cognitive abilities in children and adolescents, including the magnitude of common genetic effects and patterns of shared and unique genetic influences. Subjects included 3689 members of the Philadelphia Neurodevelopmental Cohort, a general population sample comprising those aged 8-21 years who completed an extensive battery of cognitive tests. We used genome-wide complex trait analysis to estimate the SNP-based heritability of each domain, as well as the genetic correlation between all domains that showed significant genetic influence. Several of the individual domains suggested strong influence of common genetic variants (for example, reading ability, h(2)g=0.43, P=4e-06; emotion identification, h(2)g=0.36, P=1e-05; verbal memory, h(2)g=0.24, P=0.005). The genetic correlations highlighted trait domains that are candidates for joint interrogation in future genetic studies (for example, language reasoning and spatial reasoning, r(g)=0.72, P=0.007). These results can be used to structure future genetic and neuropsychiatric investigations of diverse cognitive abilities.
Asunto(s)
Trastornos del Conocimiento/genética , Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Niño , Estudios de Cohortes , Planificación en Salud Comunitaria , Femenino , Genómica , Genotipo , Humanos , Masculino , Pruebas Neuropsicológicas , Pediatría , Fenotipo , Philadelphia/epidemiología , Análisis de Componente Principal , Adulto JovenRESUMEN
In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22.3. The lod score is robust to marker allele frequencies, phenocopy rates and age-dependent penetrance, and remains strongly positive with changes in affection status. Fourteen other markers in 21q22.3 were tested on this family, with largely positive lod scores. Five of the other 46 families also show positive, but modest lod scores with PFKL. When all 47 families are analysed together, there is little support for linkage to PFKL under homogeneity or heterogeneity using lod score analysis, but the model-free affected-pedigree-member method yields statistically significant results (p < 0.0003). Our results are consistent with the presence of a gene in 21q22.3 predisposing at least one family to bipolar disorder.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 21 , Adolescente , Adulto , Anciano , Alelos , Mapeo Cromosómico , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Escala de Lod , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Epidemiological studies have identified a small cohort of controllers of human immunodeficiency virus (HIV)-1 infection, who without treatment have no detectable virus, and others who progress at a variable rate. The objective of this study was to distinguish immune signatures in HIV controllers and progressors, by evaluating tolerogenic and immunogenic factors in untreated HIV-1 infected individuals. The recruited population was divided into putative elite controllers (PEC), long-term non-progressors (LTNP), normal progressors (NP) and fast progressors (FP). The proportion of regulatory T cells [T(regs) , CD4+ CD25+ forkhead box P3 (FoxP3+)], programmed death (PD)-1 and cytotoxic T lymphocyte antigen (CTLA)-inhibitory molecules and CD40L, CD69 and Ki67 activation markers were evaluated in peripheral blood mononuclear cells (PBMC) by flow cytometry. Significant differences were found between HIV controllers and HIV progressors, with up-regulation of T(regs) , PD-1 and CTLA-4 and decrease of CD40L expression in progressors compared with controllers. Expression of CD40L and concentrations of interleukin (IL)-6, CCL-3, and CCL-4 were significantly higher in PEC and LTNP than in NP and FP. In an attempt to convert immune signatures of progressors to those of controllers, seven agents were used to stimulate PBMC from the four cohorts. Treatment with CD40L and IL-4 or PD-1 antibodies in vitro were most effective in converting the immune signatures of progressors to those observed in controllers by down-regulating T(regs) and up-regulating CD40L expression in CD4+ T cells. The conversion concept merits translation to in vivo immune control of HIV infection.
Asunto(s)
Infecciones por VIH/inmunología , Sobrevivientes de VIH a Largo Plazo , VIH-1/inmunología , Tolerancia Inmunológica , Linfocitos T Reguladores/inmunología , Anticuerpos Monoclonales/farmacología , Antígenos CD/biosíntesis , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/inmunología , Ligando de CD40/biosíntesis , Ligando de CD40/farmacología , Antígeno CTLA-4/biosíntesis , Quimiocina CCL3/biosíntesis , Quimiocina CCL4/biosíntesis , Progresión de la Enfermedad , Citometría de Flujo , Infecciones por VIH/virología , Prueba de Histocompatibilidad , Humanos , Interleucina-4/farmacología , Interleucina-6/biosíntesis , Antígeno Ki-67/biosíntesis , Lectinas Tipo C/biosíntesis , Leucocitos Mononucleares/inmunología , Activación de Linfocitos , Polimorfismo de Nucleótido Simple , Receptores CCR5/genética , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismoRESUMEN
In spite of considerable efforts, no genes of major effect have been found across an entire diagnostic category in psychiatry. Possible reasons for this may include difficulties in defining the phenotype, the complex relationship between genotype and gene expression and population stratification. This last problem has often been managed by restricting genetic sampling to only one ethnic group. An unintended consequence of using this strategy is that the major repositories of genetic material for the study of psychiatric conditions in the United States suffer from a paucity of genetic samples from non-Caucasian groups. Thus, these groups are being relatively understudied in terms of the genetic antecedents to psychiatric disease. The authors provide solutions including the need to augment the representation of African-American, Latino and Asian-Americans among research participants; a more nuanced approach to identify ancestry; and the development of analytic and genetic strategies to handle the issue of ethnic heterogeneity in samples.
Asunto(s)
Etnicidad/genética , Predisposición Genética a la Enfermedad/etnología , Trastornos Mentales/etnología , Trastornos Mentales/genética , Heterogeneidad Genética , Humanos , National Institute of Mental Health (U.S.)/estadística & datos numéricos , Estados UnidosRESUMEN
We assessed the potential for an allogeneic-based vaccine against HIV infection in women who were allo-immunized with their partners' mononuclear leucocytes to prevent spontaneous recurrent abortion. Within 1 month of allo-immunization, there was significant upregulation in the concentrations of CD8 cell-derived suppressor factor activity, RANTES, and macrophage inflammatory proteins 1alpha and 1beta. Allo-immunization also downregulated the proportion of cells with CCR5 and CXCR4 receptors. We also found a dose-dependent decrease in HIV infectivity of CD4+ cells in vitro after allo-immunization with both primary and T-cell line adapted HIV-1. This study provides a rational basis for an alternative or complementary strategy of allo-immunization against HIV infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Quimiocinas CC/metabolismo , VIH-1/fisiología , Inmunización , Isoanticuerpos/inmunología , Factores Supresores Inmunológicos/metabolismo , Aborto Habitual/inmunología , Aborto Habitual/terapia , Antígenos CD4/inmunología , Antígenos CD4/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Células Cultivadas , Quimiocina CCL4 , Quimiocina CCL5/metabolismo , Quimiocinas CC/inmunología , Femenino , Regulación de la Expresión Génica , Infecciones por VIH/inmunología , VIH-1/inmunología , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/trasplante , Proteínas Inflamatorias de Macrófagos/metabolismo , Masculino , Embarazo , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Factores Supresores Inmunológicos/inmunología , Replicación ViralRESUMEN
A functional comparison was made between a monoclonal secretory antibody generated in transgenic plants and its parent murine IgG antibody.The affinity constants of both antibodies for a Streptococcus mutans adhesion protein were similar. However the secretory antibody had a higher functional affinity due to its dimeric structure. In the human oral cavity, the secretory antibody survived for up to three days, compared with one day for the IgG antibody. The plant secretory antibody afforded specific protection in humans against oral streptococcal colonization for at least four months. We demonstrate that transgenic plants can be used to produce high affinity, monoclonal secretory antibodies that can prevent specific microbial colonization in humans. These findings could be extended to the immunotherapeutic prevention of other mucosal infections in humans and animals.
Asunto(s)
Anticuerpos Antibacterianos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Caries Dental/prevención & control , Inmunización Pasiva , Inmunoglobulina A Secretora/uso terapéutico , Plantas Modificadas Genéticamente , Proteínas Recombinantes/uso terapéutico , Administración Tópica , Animales , Anticuerpos Antibacterianos/biosíntesis , Anticuerpos Antibacterianos/genética , Anticuerpos Monoclonales/biosíntesis , Anticuerpos Monoclonales/genética , Clorhexidina/análogos & derivados , Clorhexidina/farmacología , Placa Dental/microbiología , Estabilidad de Medicamentos , Humanos , Inmunoglobulina A Secretora/biosíntesis , Inmunoglobulina A Secretora/genética , Ratones , Proteínas Recombinantes/biosíntesis , Streptococcus mutans/inmunologíaRESUMEN
Prevention of sexually transmitted HIV infection was investigated in macaques by immunization with a recombinant SIV (simian immunodeficiency virus) envelope gp 120 and core p27 vaccine. In two independent series of experiments, we used the novel targeted iliac lymph node (TILN) route of immunization, aiming close to the iliac lymph nodes draining the genitorectal mucosa. Rectal challenge with the SIVmac 32H J5 molecular clone in two series induced total protection in four out of seven macaques immunized by TILN, compared with infection in 13 of 14 unimmunized macaques or immunized by other routes (P = 0.025). The remaining three macaques showed either a decrease in viral load ( > 90%) or transient viremia, indicating that all seven TILN-immunized macaques showed total or partial protection (P = 0.001). Protection was associated with significant increase in the iliac lymph nodes of IgA antibody-secreting cells to p27 (P < 0.02), CD8-suppressor factor (P < 0.01), and the chemokines RANTES and MIP-1 beta (P < 0.01).
Asunto(s)
Mucosa Intestinal/inmunología , Ganglios Linfáticos/inmunología , Vacunas contra el SIDAS/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas Sintéticas/inmunología , Animales , Anticuerpos Antivirales/biosíntesis , Células Productoras de Anticuerpos/inmunología , Linfocitos B/inmunología , Quimiocinas/inmunología , Colorantes Fluorescentes , Íleon/inmunología , Ganglios Linfáticos/virología , Macaca mulatta , Masculino , Factores Supresores Inmunológicos/inmunología , Linfocitos T/inmunologíaRESUMEN
HIV-1 is predominantly transmitted through mucosal tissues, targeting CD4(+)CCR5(+) T cells, 50% of which are destroyed within 2 weeks of infection. Conventional vaccination strategies have so far failed to prevent HIV-1 infection. Neither antibodies nor cytotoxic lymphocytes are capable of mounting a sufficiently rapid immune response to prevent early destruction of these cells. However, innate immunity is an early-response system, largely independent of prior encounter with a pathogen. Innate immunity can be classified into cellular, extracellular, and intracellular components, each of which is exemplified in this review by γδ T cells, CC chemokines, and APOBEC3G, respectively. First, γδ T cells are found predominantly in mucosal tissues and produce cytokines, CC chemokines, and antiviral factors. Second, the CC chemokines CCL-3, CCL-4, and CCL-5 can be upregulated by immunization of macaques with SIVgp120 and gag p27, and these can bind and downmodulate CCR5, thereby inhibiting HIV-1 entry into the host cells. Third, APOBEC3G is generated and maintained following rectal mucosal immunization in rhesus macaques for over 17 weeks, and the innate anti-SIV factor is generated by CD4(+)CD95(+)CCR7(-) effector memory T cells. Thus, innate anti-HIV-1 or SIV immunity can be linked with immune memory, mediated by CD4(+) T cells generating APOBEC3G. The multiple innate functions may mount an early anti-HIV-1 response and either prevent viral transmission or contain the virus until an effective adaptive immune response develops.
Asunto(s)
Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , VIH-1/inmunología , Inmunidad Innata , Desaminasa APOBEC-3G , Animales , Linfocitos T CD4-Positivos/inmunología , Quimiocinas CC/inmunología , Citidina Desaminasa/inmunología , Citidina Desaminasa/metabolismo , Humanos , Interferones/inmunología , Células de Langerhans/fisiología , Macaca mulatta/inmunología , Macrófagos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores CCR5/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Replicación ViralRESUMEN
Heterosexual transmission through the cervico-vaginal mucosa is the principal route of human immunodeficiency virus (HIV) infection in Africa and is increasing in the United States and Europe. Vaginal immunization with simian immunodeficiency virus (SIV) had not yet been studied in nonhuman primates. Immune responses in macaques were investigated by stimulation of the genital and gut-associated lymphoid tissue with a recombinant, particulate SIV antigen. Vaginal, followed by oral, administration of the vaccine elicited three types of immunity: (i) gag protein p27-specific, secretory immunoglobulin A (IgA) and immunoglobulin G (IgG) in the vaginal fluid, (ii) specific CD4+ T cell proliferation and helper function in B cell p27-specific IgA synthesis in the genital lymph nodes, and (iii) specific serum IgA and IgG, with CD4+ T cell proliferative and helper functions in the circulating blood.
Asunto(s)
Productos del Gen gag/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas Sintéticas/inmunología , Administración Oral , Animales , Anticuerpos Antivirales/análisis , Linfocitos T CD4-Positivos/inmunología , Femenino , Inmunidad , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Macaca mulatta , Membrana Mucosa/inmunología , Proteínas Recombinantes/inmunología , Saliva/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Vacunas Sintéticas/administración & dosificación , Vagina/inmunologíaRESUMEN
Four transgenic Nicotiana tabacum plants were generated that expressed a murine monoclonal antibody kappa chain, a hybrid immunoglobulin A-G heavy chain, a murine joining chain, and a rabbit secretory component, respectively. Successive sexual crosses between these plants and filial recombinants resulted in plants that expressed all four protein chains simultaneously. These chains were assembled into a functional, high molecular weight secretory immunoglobulin that recognized the native streptococcal antigen I/II cell surface adhesion molecule. In plants, single cells are able to assemble secretory antibodies, whereas two different cell types are required in mammals. Transgenic plants may be suitable for large-scale production of recombinant secretory immunoglobulin A for passive mucosal immunotherapy. Plant cells also possess the requisite mechanisms for assembly and expression of other complex recombinant protein molecules.
Asunto(s)
Inmunoglobulina A Secretora/biosíntesis , Fragmentos de Inmunoglobulinas/biosíntesis , Plantas Modificadas Genéticamente/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/biosíntesis , Inmunoglobulina A Secretora/genética , Inmunoglobulina G/biosíntesis , Cadenas Pesadas de Inmunoglobulina/biosíntesis , Región de Unión de la Inmunoglobulina/biosíntesis , Cadenas Ligeras de Inmunoglobulina/biosíntesis , Ratones , Datos de Secuencia Molecular , Plantas Tóxicas , Conejos , Componente Secretorio/biosíntesis , NicotianaRESUMEN
Pyrochlore systems are ideally suited to the exploration of geometrical frustration in three dimensions, and their rich phenomenology encompasses topological order and fractional excitations. Classical spin ices provide the first context in which it is possible to control emergent magnetic monopoles, and anisotropic exchange leads to even richer behaviour associated with large quantum fluctuations. Whether the magnetic ground state of Yb2Ti2O7 is a quantum spin liquid or a ferromagnetic phase induced by a Higgs transition appears to be sample dependent. Here we have determined the role of structural defects on the magnetic ground state via the diffuse scattering of neutrons. We find that oxygen vacancies stabilise the spin liquid phase and the stuffing of Ti sites by Yb suppresses it. Samples in which the oxygen vacancies have been eliminated by annealing in oxygen exhibit a transition to a ferromagnetic phase, and this is the true magnetic ground state.
Asunto(s)
Trastorno Bipolar/genética , Cromosoma X , Trastorno Bipolar/enzimología , Trastorno Bipolar/etiología , Femenino , Ligamiento Genético , Marcadores Genéticos , Glucosafosfato Deshidrogenasa/genética , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Deficiencia de Glucosafosfato Deshidrogenasa/genética , Humanos , MasculinoRESUMEN
The earliest step in microbial infection is adherence by specific microbial adhesins to the mucosa of the oro-intestinal, nasorespiratory, or genitourinary tract. We inhibited binding of a cell surface adhesin of Streptococcus mutans to salivary receptors in vitro, as measured by surface plasmon resonance, using a synthetic peptide (p1025) corresponding to residues 1025-1044 of the adhesin. Two residues within p1025 that contribute to binding (Q1025, E1037) were identified by site-directed mutagenesis. In an in vivo human streptococcal adhesion model, direct application of p1025 to the teeth prevented recolonization of S. mutans but not Actinomyces, as compared with a control peptide or saline. This novel antimicrobial strategy, applying competitive peptide inhibitors of adhesion, may be used against other microorganisms in which adhesins mediate colonization of mucosal surfaces.
Asunto(s)
Antibacterianos/farmacología , Adhesión Bacteriana/efectos de los fármacos , Cariostáticos/uso terapéutico , Glicoproteínas de Membrana , Péptidos/farmacología , Péptidos/uso terapéutico , Diente/microbiología , Actinomyces/efectos de los fármacos , Actinomyces/aislamiento & purificación , Administración Tópica , Secuencia de Aminoácidos , Antibacterianos/uso terapéutico , Proteínas Bacterianas/efectos de los fármacos , Proteínas Bacterianas/metabolismo , Cariostáticos/farmacología , Caries Dental/microbiología , Caries Dental/prevención & control , Placa Dental/microbiología , Epítopos/metabolismo , Humanos , Sueros Inmunes/análisis , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Péptidos/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Infecciones Estreptocócicas/prevención & control , Streptococcus mutans/efectos de los fármacos , Streptococcus mutans/fisiología , Diente/efectos de los fármacosRESUMEN
Magnetic Archimedes Coriolis (MAC) waves are omnipresent in several geophysical and astrophysical flows such as the solar tachocline. In the present study, we use linear spectral theory (LST) and investigate the energy partition, scale by scale, in MAC weak wave turbulence for a Boussinesq fluid. At the scale k^{-1}, the maximal frequencies of magnetic (Alfvén) waves, gravity (Archimedes) waves, and inertial (Coriolis) waves are, respectively, V_{A}k,N, and f. By using the induction potential scalar, which is a Lagrangian invariant for a diffusionless Boussinesq fluid [Salhi et al., Phys. Rev. E 85, 026301 (2012)PLEEE81539-375510.1103/PhysRevE.85.026301], we derive a dispersion relation for the three-dimensional MAC waves, generalizing previous ones including that of f-plane MHD "shallow water" waves [Schecter et al., Astrophys. J. 551, L185 (2001)AJLEEY0004-637X10.1086/320027]. A solution for the Fourier amplitude of perturbation fields (velocity, magnetic field, and density) is derived analytically considering a diffusive fluid for which both the magnetic and thermal Prandtl numbers are one. The radial spectrum of kinetic, S_{κ}(k,t), magnetic, S_{m}(k,t), and potential, S_{p}(k,t), energies is determined considering initial isotropic conditions. For magnetic Coriolis (MC) weak wave turbulence, it is shown that, at large scales such that V_{A}k/fâª1, the Alfvén ratio S_{κ}(k,t)/S_{m}(k,t) behaves like k^{-2} if the rotation axis is aligned with the magnetic field, in agreement with previous direct numerical simulations [Favier et al., Geophys. Astrophys. Fluid Dyn. (2012)] and like k^{-1} if the rotation axis is perpendicular to the magnetic field. At small scales, such that V_{A}k/fâ«1, there is an equipartition of energy between magnetic and kinetic components. For magnetic Archimedes weak wave turbulence, it is demonstrated that, at large scales, such that (V_{A}k/Nâª1), there is an equipartition of energy between magnetic and potential components, while at small scales (V_{A}k/Nâ«1), the ratio S_{p}(k,t)/S_{κ}(k,t) behaves like k^{-1} and S_{κ}(k,t)/S_{m}(k,t)=1. Also, for MAC weak wave turbulence, it is shown that, at small scales (V_{A}k/sqrt[N^{2}+f^{2}]â«1), the ratio S_{p}(k,t)/S_{κ}(t) behaves like k^{-1} and S_{κ}(k,t)/S_{m}(k,t)=1.
RESUMEN
The appalling toll on the populations of developing countries as a result of the HIV epidemic shows no signs of abatement. While costly drug therapies are effective in developed nations, the sheer scale of the epidemic elsewhere makes the need for a vaccine an ever more urgent goal. The prevalent DNA prime-viral boost strategy aims to elicit cytotoxic lymphocytes (CTL) against HIV, but this approach is undermined by the rapid mutation of HIV, which thereby escapes CTL control. Alloimmunity has been found to be protective in vertical transmission from infected mothers to their babies, in alloimmunization of women with their partners' mononuclear cells, and in monkeys immunized with SIV grown in human T-cells. Vaginal mucosal immunization, as a result of unprotected sex with a regular partner, induced in vitro protection against HIV infection, and this was confirmed in macaques. The second type of natural protection is found in persons with the homozygous 32 CCR5 mutation, a 32-base-pair deletion of the CCR5 gene, which results in a lack of cell-surface expression of CCR5, which is associated with an increase in CC chemokines and the development of CCR5 antibodies. These two 'experiments of nature' have been used to develop vaccine strategies--first, in vaginal immunization of macaques with CCR5 peptides, in addition to HIV envelope (env) and SIV core (gag) antigens, all of which were linked to the 70-kD heat-shock protein (HSP70); and second, in mucosal allo-immunization of macaques, which also gave rise to in vitro protection from infection. Immunization with this vaccine elicited serum and vaginal IgG and IgA antibodies, IFNgamma- and IL-12-producing cells, and increased concentrations of CCL-3 and CCL-4. Vaginal challenge with a simian immunodeficiency virus engineered to carry a human envelope protein (SHIV 89.6) showed significant clearance of SHIV in the immunized macaques. This platform strategy will now be developed to activate the co-stimulatory pathways with the aim of enhancing the primary allogeneic and CCR5-directed responses which are involved in natural protection against HIV infection.
Asunto(s)
Vacunas contra el SIDA , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , Inmunidad Mucosa/fisiología , Vacunas contra el SIDAS/inmunología , Adyuvantes Inmunológicos , Animales , Quimiocinas/fisiología , Regulación hacia Abajo , Femenino , Antígenos VIH/inmunología , Infecciones por VIH/prevención & control , Proteínas HSP70 de Choque Térmico/inmunología , Humanos , Inmunidad Innata/fisiología , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Macaca , Masculino , Receptores del VIH/fisiología , Factores Supresores Inmunológicos/inmunología , Linfocitos T Citotóxicos/fisiología , Vagina/inmunologíaRESUMEN
We consider horizontal linear shear flow (shear rate denoted by Λ) under vertical uniform rotation (ambient rotation rate denoted by Ω(0)) and vertical stratification (buoyancy frequency denoted by N) in unbounded domain. We show that, under a primary vertical velocity perturbation and a radial density perturbation consisting of a one-dimensional standing wave with frequency N and amplitude proportional to w(0)sin(ÉNx/w(0))≈ÉNx(âª1), where x denotes the radial coordinate and É a small parameter, a parametric instability can develop in the flow, provided N(2)>8Ω(0)(2Ω(0)-Λ). For astrophysical accretion flows and under the shearing sheet approximation, this implies N(2)>8Ω(0)(2)(2-q), where q=Λ/Ω(0) is the local shear gradient. In the case of a stratified constant angular momentum disk, q=2, there is a parametric instability with the maximal growth rate (σ(m)/É)=3â[3]/16 for any positive value of the buoyancy frequency N. In contrast, for a stratified Keplerian disk, q=1.5, the parametric instability appears only for N>2Ω(0) with a maximal growth rate that depends on the ratio Ω(0)/N and approaches (3â[3]/16)É for large values of N.
RESUMEN
The rectal mucosa is one of the routes of transmission of the HIV virus, although the mechanism of transmission is unknown. We carried out an immunohistological investigation of human rectal epithelium to detect CD4 glycoprotein and Fc receptors (FcR) for immunoglobulin G which may be involved in HIV infection. CD4 was not detected by monoclonal antibodies (MAb) in normal rectal epithelial cells, although CD4+ mononuclear cells were found in the lamina propria of the rectum. FcR3 and FcR2 were, however, detected in surface or crypt epithelial cells of rectal mucosa, using MAb to CD16 and CD32, respectively. In addition, CD16 messenger RNA (mRNA) was found in surface and crypt epithelial cells by in situ hybridization using an RNA probe. FcR3 and FcR2 were also detected in fetal recto-colonic tissue by immunohistology, suggesting that these are constitutive receptors. FcR3 and FcR2 gene transcripts were then demonstrated in fetal recto-colonic tissue using the polymerase chain reaction to amplify a portion of FcR3 and FcR2 coding sequences in complementary DNA (cDNA) prepared from fetal RNA. These findings suggest the possibility that rectal transmission of HIV-antibody complexes might be facilitated by the expression of FcR3 and FcR2 in rectal epithelial cells.
Asunto(s)
Antígenos CD4/análisis , Receptores Fc/análisis , Recto/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Anticuerpos Monoclonales/metabolismo , Complejo Antígeno-Anticuerpo/inmunología , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/inmunología , Secuencia de Bases , Northern Blotting , Antígenos CD4/genética , Antígenos CD4/inmunología , Linfocitos T CD4-Positivos/inmunología , Epitelio/inmunología , Expresión Génica/inmunología , VIH/inmunología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Inmunohistoquímica , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Sondas ARN/genética , Receptores Fc/genética , Receptores Fc/inmunología , Receptores de IgG , Recto/embriología , Recto/metabolismoRESUMEN
OBJECTIVE: Sexual transmission of HIV is the most common route of HIV transmission throughout the world. To prevent sexually transmitted HIV infection, a vaccine is urgently needed. A previous report demonstrated the targeted immunization of the iliac lymph nodes with simian immunodeficiency virus (SIV) subunits protects rhesus macaques from rectal challenge with SIV. We sought to determine whether this immunization strategy could protect rhesus macaques from vaginal challenge with SIV. DESIGN: Macaques were immunized with either whole-killed SIV or envelope and core subunit antigen vaccines. Using three independent groups, with three macaques in each group, macaques were immunized by the targeted iliac lymph-node (TILN) route, injecting the vaccine close to the iliac lymph nodes that drain the genital tract. RESULTS: The TILN immunization procedure induced high-titer SIV-specific immunoglobulin (Ig) G antibodies in serum in all animals and anti-SIV IgG and IgA antibodies in the cervicovaginal secretions of most animals. After a series of three or four TILN immunizations, the animals were intravaginally challenged with SIVmac251. All animals became virus isolation-positive, except one animal immunized with SIV p27 and gp120. This animal was virus isolation-negative but SIV DNA proviral sequences were detected in peripheral blood mononuclear cells. CONCLUSIONS: In this series of studies, reliable protection from vaginal transmission of SIV was not achieved by the TILN immunization procedure.